title: Modulation of innate and adaptive immune responses by tofacitinib (CP-690,550).
abstract: Inhibitors of the JAK family of nonreceptor tyrosine kinases have demonstrated clinical efficacy in rheumatoid arthritis and other inflammatory disorders; however, the precise mechanisms by which JAK inhibition improves inflammatory immune responses remain unclear. In this study, we examined the mode of action of tofacitinib (CP-690,550) on JAK/STAT signaling pathways involved in adaptive and innate immune responses. To determine the extent of inhibition of specific JAK/STAT-dependent pathways, we analyzed cytokine stimulation of mouse and human T cells in vitro. We also investigated the consequences of CP-690,550 treatment on Th cell differentiation of naive murine CD4(+) T cells. CP-690,550 inhibited IL-4-dependent Th2 cell differentiation and interestingly also interfered with Th17 cell differentiation. Expression of IL-23 receptor and the Th17 cytokines IL-17A, IL-17F, and IL-22 were blocked when naive Th cells were stimulated with IL-6 and IL-23. In contrast, IL-17A production was enhanced when Th17 cells were differentiated in the presence of TGF-β. Moreover, CP-690,550 also prevented the activation of STAT1, induction of T-bet, and subsequent generation of Th1 cells. In a model of established arthritis, CP-690,550 rapidly improved disease by inhibiting the production of inflammatory mediators and suppressing STAT1-dependent genes in joint tissue. Furthermore, efficacy in this disease model correlated with the inhibition of both JAK1 and JAK3 signaling pathways. CP-690,550 also modulated innate responses to LPS in vivo through a mechanism likely involving the inhibition of STAT1 signaling. Thus, CP-690,550 may improve autoimmune diseases and prevent transplant rejection by suppressing the differentiation of pathogenic Th1 and Th17 cells as well as innate immune cell signaling.
authors.affiliation: Molecular Immunology and Inflammation Branch, National Institute of Arthritis and Musculoskeletal and Skin Diseases, National Institutes of Health, Bethesda, MD 20892, USA. ghoreschik@mail.nih.gov
authors.forename: Kamran
authors.initials: K
authors.lastname: Ghoreschi
authors.forename: Michael I
authors.initials: MI
authors.lastname: Jesson
authors.forename: Xiong
authors.initials: X
authors.lastname: Li
authors.forename: Jamie L
authors.initials: JL
authors.lastname: Lee
authors.forename: Sarbani
authors.initials: S
authors.lastname: Ghosh
authors.forename: Jason W
authors.initials: JW
authors.lastname: Alsup
authors.forename: James D
authors.initials: JD
authors.lastname: Warner
authors.forename: Masao
authors.initials: M
authors.lastname: Tanaka
authors.forename: Scott M
authors.initials: SM
authors.lastname: Steward-Tharp
authors.forename: Massimo
authors.initials: M
authors.lastname: Gadina
authors.forename: Craig J
authors.initials: CJ
authors.lastname: Thomas
authors.forename: John C
authors.initials: JC
authors.lastname: Minnerly
authors.forename: Chad E
authors.initials: CE
authors.lastname: Storer
authors.forename: Timothy P
authors.initials: TP
authors.lastname: LaBranche
authors.forename: Zaher A
authors.initials: ZA
authors.lastname: Radi
authors.forename: Martin E
authors.initials: ME
authors.lastname: Dowty
authors.forename: Richard D
authors.initials: RD
authors.lastname: Head
authors.forename: Debra M
authors.initials: DM
authors.lastname: Meyer
authors.forename: Nandini
authors.initials: N
authors.lastname: Kishore
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Shea
mesh_terms: D056704:Adaptive Immunity / Q000235:genetics; D000818:Animals; D001169:Arthritis, Experimental / Q000188:drug therapy / Q000201:enzymology / Q000276:immunology*; D030161:Avian Proteins / Q000633:toxicity*; D002478:Cells, Cultured; D002645:Chickens; D024043:Collagen Type II / Q000633:toxicity*; D006801:Humans; D007113:Immunity, Innate / Q000235:genetics; D053616:Janus Kinase 3 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics; D020935:MAP Kinase Signaling System / Q000235:genetics / Q000276:immunology; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D008811:Mice, Inbred DBA; D018345:Mice, Knockout; D010880:Piperidines; D047428:Protein Kinase Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D011743:Pyrimidines / Q000008:administration & dosage* / Q000627:therapeutic use; D011758:Pyrroles / Q000008:administration & dosage* / Q000627:therapeutic use
chemical_list: D030161:Avian Proteins; D024043:Collagen Type II; D010880:Piperidines; D047428:Protein Kinase Inhibitors; D011743:Pyrimidines; D011758:Pyrroles; C479163:tofacitinib; C507935:Jak3 protein, mouse; D053616:Janus Kinase 3